Structure and Dynamics of Alzheimer's Associated Amyloid-Beta Peptide

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Alzheimer's disease and other neurodegenerative illnesses are among the leading causes of death in the developed world, yet there are currently no treatments available. One of the characteristics of Alzheimer's disease is the formation of neurotoxic fibrils and oligomers through the aggregation of the intrinsically disordered protein (IDP) amyloid-β. While understanding this process has seen widespread experimental interest, it is becoming evident that molecular simulations can provide a unique, in-depth description of these events. A major challenge in this context has been in modelling not only the thermodynamic and structural, but also kinetic properties of the system. The latter requires a discretisation into individual states, which is typically difficult to achieve for IDPs. However, many recent developments in the analysis of dynamical systems as well as the growing accessibility of computational resources have made addressing the problem of generating high quality ensembles possible. We here present an in-depth description of an amyloid-β 42 ensemble acquired from all-atom, explicit solvent molecular dynamics simulations totaling 240 μs using a Markov state model and validate our results using data from NMR measurements. We then correlate our findings with information on the subsequences known to be important for aggregation. Taken together, these results could aid in the understanding of the oligomerisation and fibrillisation processes, and subsequently inform drug developments targeting specific epitopes along the sequence of this aggregation-prone disordered protein.